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Roles of Carbon monoxide in regulation of sinusoidal blood flow and bile excretion

一氧化碳在调节血窦血流和胆汁排泄中的作用

基本信息

批准号：
09470143
负责人：
SUEMATSU Makoto
金额：
$ 3.26万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470143/
关键词：
heme oxygenase Carbon monoxide Nitric oxide cytochrome P450 Ito Cell guanylate cyclase calcium hepatocytes ヘムオキシゲナーゼ微小循環血管内皮細胞ヘモグロビン

项目摘要

This project aimed to examine whether carbon monoxide (CO), a product of heme oxygenase reaction, controls the contractility of bile canaliculus (BC) in hepatocytes and thus determine the ability of bile excretion in the liver. When BCs associated with the couplet cells in cultured rat hepatocyte suspension were observed using time-lapse video microscopy, they exhibited periodical contractions with most probable interval of 6 mm under our experimental conditions. Addition of 1 muM zinc protoporphyrin IX (ZnPP), a potent inhibitor of heme oxygenase, to the culture medium elicited a 40% shortening of the interval time together with an increase in intracellular calcium concentrations, while the same concentration of iron protoporphyrin IX did not induce such changes. The ZnPP-elicited increases in both contractile frequency and intracellular calcium concentrations were attenuated by the addition of 1 muM CO or 50 muM 1,2-bis(2-aininophenoxy) ethane-tetrraacetate, a calcium chelator Clotrimazole or metyrapone, inhibitors of cytochrome P450-dependent monooxygenase activities, also attenuated the ZnPP-induced elevation of the contractile frequency. On the other hand, intracellular cGM7P contents were not altered significantly by the application of ZnPP nor by CO, suggesting that the role of soluble guanylate cyclase is little, if any. These results indicate that CO generated by heme oxygenase controls the BC function by changing intracellular calcium concentrations presumably through a mechanism involving the cytochrome P450 reaction.

本项目旨在研究血红素加氧酶反应产物一氧化碳（CO）是否控制肝细胞内胆小管（BC）的收缩性，从而确定肝脏排泄胆汁的能力。当使用延时视频显微镜观察培养的大鼠肝细胞悬浮液中与配对细胞相关的BC时，在我们的实验条件下，它们表现出周期性收缩，最可能的间隔为6毫米。在培养基中添加 1 μM 锌原卟啉 IX (ZnPP)（一种有效的血红素加氧酶抑制剂），可使间隔时间缩短 40%，同时细胞内钙浓度增加，而相同浓度的铁原卟啉 IX 不会引起这种变化。添加 1 μM CO 或 50 μM 1,2-双（2-氨基苯氧基）乙烷四乙酸酯、钙螯合剂克霉唑或美替拉酮、细胞色素 P450 依赖性单加氧酶活性抑制剂，可减弱 ZnPP 引起的收缩频率和细胞内钙浓度的增加，也减弱了 ZnPP 诱导的收缩频率和细胞内钙浓度的增加。收缩频率升高。另一方面，细胞内 cGM7P 含量并未因 ZnPP 的应用或 CO 的应用而发生显着改变，这表明可溶性鸟苷酸环化酶的作用即使有的话也是很小的。这些结果表明，血红素加氧酶产生的 CO 可能通过涉及细胞色素 P450 反应的机制改变细胞内钙浓度来控制 BC 功能。